Process of making substituted pyrazoles

Details Process of making substituted pyrazoles Process of making substituted pyrazoles

2000-10-27

2002-06-18

Shah, Mukund J. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S405000, C546S144000, C546S167000, C546S275400, C548S364100, C548S371400, C548S376100, C548S373100, C548S377100

Reexamination Certificate

active

06407238

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel synthesis of substituted aryl and heteroaryl pyrazole compounds of the formula (I) described herein.
BACKGROUND
The aryl and heteroaryl pyrazole structure is found in a large number and variety of compounds that possess important biological activities and pharmacological properties. Makino, K. et al.
J. Heterocyclic Chem
. 1998, 35, 489; Elguero,
J. Compr. Heterocycl. Chem
. II 1996, 3, 1. For example, WO 98/52558 and WO 99/23091 disclose heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases. U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
The synthesis of this important family of compounds is well reviewed. See Makino, K. et al. supra, Takagi, K. et al.
J. Heterocyclic Chem
. 1996, 33, 1003; El-Rayyes, N. R. et al.
Synthesis
1985, 1028; Sammes, M. P. et al.
Advances in Heterocyclic Chemistry
, Vol 34, Academic Press, 1983; Behr, L. C. et al.
The Chemistry of Heterocyclic Compounds
, Weissberger, A., ed., Interscience Publishers, John Wiley and Sons, 1967. The conventional approach for pyrazole synthesis is the condensation of an aryl hydrazine with 1,3-diketones or their equivalents, such as &bgr;-ketoesters, &bgr;-cyanoketones and others. However, aryl hydrazines have not been widely available by convenient, scalable chemistry. Buchwald and Hartwig have recently described a general and practical synthesis of N-arylated benzophenone hydrazones. Buchwald, S. L. et al.
J. Am. Chem. Soc
. 1998, 120, 6621; Hartwig, J. F.
Angew. Chem., Int. Ed
. 1998, 37, 2090.
Unfortunately, their hydrolysis to N-aryl hydrazines has not been demonstrated. There is therefore a clear need for a synthesis of substituted pyrazoles which overcomes limitations of well known syntheses.
SUMMARY OF THE INVENTION
The present invention addresses the need in the art for a versatile new synthesis of substituted pyrazoles of the formula (I):
wherein R
1
, R
2
, R
3
and R
4
are defined herein below, by providing for the first time a process of making a variety of pyrazoles from substituted benzophenone hydrazones with different 1,3-bifunctional groups.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
In the present invention, it was postulated that upon treatment of such hydrazones with dicarbonyl compounds or related functionalities apparent to the skilled artisan, a transhydrazonation reaction would take place
3a
, leading eventually to pyrazole compounds of the formula (I). Such a synthesis will benefit from the demonstrated palladium catalyzed cross couplings of benzophenone hydrazone to various aryl halides and overcomes limitations associated with the availability of aryl and heteroaryl hydrazines.
4
The novel process of the invention also provides product compounds with a desirable high regio specificity as shown in schemes 1-4 below.
In one embodiment of the invention there is provided the process of making a pyrazole compound of the formula (I):
wherein R
1
, R
2
, R
3
and R
4
are defined as follows:
each R
1
and R
3
are independently chosen from:
amino and C
1-10
alkyl optionally partially or fully halogenated and optionally substituted with one to three C
3-10
cycloalkanyl, C
1-6
alkoxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups chosen from halogen, C
1-6
alkyl which is optionally partially or fully halogenated, C
3-8
cycloalkanyl, C
5-8
cycloalkenyl and C
1-3
alkoxy which is optionally partially or fully halogenated; wherein both R
1
and R
3
cannot simultaneously be amino;
R
2
is chosen from:
hydrogen, C
1-6
branched or unbranched alkyl optionally partially or fully halogenated and aryl optionally partially or fully halogenated;
R
4
is chosen from:
phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, C
1-6
branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C
1-5
alkyl, naphthyl C
1-5
alkyl, halogen, hydroxy, oxo, nitrile, C
1-3
alkoxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH
2
C(O), a mono- or di-(C
1-3
alkyl) aminocarbonyl, C
1-5
alkyl—C(O)—C
1-4
alkyl, amino-C
1-5
alkyl, mono- or di-(C
1-3
alkyl) amino-C
1-5
alkyl, amino-S(O)
2
, di-(C
1-3
alkyl)amino-S(O)
2
, R
7
—C
1-5
alkyl, R
8
—C
1-5
alkoxy, R
9
—C(O)—C
1-5
alkyl, R
10
—C
1-5
alkyl(R
11
)N or carboxy-mono-or di-(C
1-5
alkyl)-amino;
a fused aryl chosen from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl chosen from cyclopentenopyridinyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C
1-6
alkyl which is optionally partially or fully halogenated, halogen, nitrile, C
1-3
alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, mono- or di-(C
1-3
alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH
2
C(O), mono- or di-(C
1-3
alkyl) aminocarbonyl, C
1-4
alkyl-OC(O), C
1-5
alkyl-C(O)-C
1-4
alkyl, amino-C
1-5
alkyl and mono- or di-(C
1-3
)alkylamino-C
1-5
alkyl;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C
1-3
alkyl groups;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C
1-3
alkyl groups; and
C
1-6
alkyl branched or unbranched and optionally partially or fully halogenated;
R
11
is chosen from hydrogen and C
1-4
branched or unbranched alkyl which may optionally be partially or fully halogenated;
each R
7
, R
8
, R
9
, R
10
, is independently chosen from:
morpholine, piperidine, piperazine, imidazole and tetrazole;
wherein said method comprises:
reacting a compound of the formula (II) with a compound of the formula (III)

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